Acyl benzo[d]thiazol-2-amine and their methods of use

ABSTRACT

Disclosed are acyl benzo[d]thiazol-2-amines having a structure according to formula (I): 
     
       
         
         
             
             
         
       
     
     including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. The compounds may be useful for the treatment of various diseases including, for example, neurological disorders such as amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, and cancers such as melanoma, breast cancer, brain cancer, and prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/373,091 filed Aug. 10, 2016, which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention describes novel acyl benzo[d]thiazol-2-amines and their method use for the treatment of cancers, including melanoma, and other diseases.

BACKGROUND OF THE INVENTION

A recently conducted Phase 0 human clinical trial of riluzole (Rilutek™) demonstrated dramatic efficacy in certain melanoma patients after only 14 days of treatment. Riluzole, the only FDA approved drug to treat amyotrophic lateral sclerosis (ALS), showed clinical or radiologic evidence of tumor response in four of 12 patients with Stage III and IV melanoma, cancer with a poor prognosis and severely limited treatment options.

It is clear that the repositioned use of riluzole for melanoma or other cancers will be significantly constrained due to high levels of variability in hepatic metabolism of the drug as is the case for its clinical use for ALS. We describe herein novel acyl benzo[d]thiazol-2-amines analogous to riluzole in order to improve the clinical efficacy of riluzole-based therapy, increase patient compliance, and relieve human suffering. Metastatic melanoma has few treatment options, and the current therapeutic standard of care is dacarbazine which is a highly cytotoxic drug with severe side effects including vomiting, headache and hair loss. Treatment with dacarbazine has a median progression-free enhancement of survival time of only 1.5 months. Riluzole (Rilutek™) is a generally non-toxic drug and currently the only FDA-approved treatment for amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).

We have recently shown that riluzole has dramatic anti-melanoma activity in vitro cellular assays, in mice and in a Phase 0 human clinical trial. In the clinic, four of twelve melanoma patients showed significant clinical or radiologic evidence of Stage III and IV tumor response. These results, along with the mild side-effect profile that riluzole has shown among ALS patients, suggests that this drug has significant potential for use as an improved treatment for :metastatic melanoma. However, the therapeutic utility of riluzole itself in ALS and eventually for melanoma is very constrained by rapid first-pass metabolism in the liver and an exceptionally high level of patient-to-patient variability in the extent of the Cyp1A2-mediated oxidative metabolism that is observed.

Riluzole is also believed to be clinically relevant in additional disease states, including a variety of central nervous system (“CNS”) and depression/anxiety states. These include, but are not limited to, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, and Huntington's disease. However, riluzole can have issues in liver metabolism. The acyl benzo[d]thiazol-2-amine of the disclosure will provide more predictable pharmacokinetic properties and metabolic profiles, leading to an improved therapeutic effect in each of the aforementioned disease states.

It has also been demonstrated that riluzole is clinically relevant to generalized anxiety disorder (GAD) and is useful for the attenuation of presynaptic glutamate release. Riluzole is also useful for the normalization, enhancement or potentiation of the uptake of glutamate by glia (Coric et al. U.S. Pat. No. 8,778,979).

There is a long felt need for new treatments for melanoma that are both disease-modifying and effective in treating patients that are refractory to current treatments. The present invention addresses the need to identify new treatments for melanoma by identifying novel acyl benzo[d]thiazol-2-amine which possess enhanced stability to hepatic metabolism, are delivered into systemic circulation by oral administration, and are effective in treating or mitigating conditions in which Riluzole is clinically relevant. The compounds of the present invention may also treat or prevent various neurological or CNS states as well as depression/anxiety states.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward acyl benzo[d]thiazol-2-amines of formula (I),

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R¹, R², and R⁴ are each independently selected from the group consisting of hydrogen, halogen, C₁-C₆ linear alkyl, C₁-C₆ linear alkenyl, C₃-C₇ branched alkyl, C₃-C₇ branched alkenyl, C₃-C₇ cycloalkyl, C₁-C₆ linear alkoxy, C₃-C₇ branched alkoxy, C₃-C₇ cycloalloxy, —S—C₁-C₆ linear alkyl, —S—C₃-C₇ branched alkyl, —S—C₃-C₇ cycloalkyl, —SO₂—C₁-C₆ linear alkyl, —SO₂—C₃-C₇ branched alkyl, —SO₂—C₃-C₇ cycloalkyl, OCF₃, OCHF₂, OCH₂F, SCF₃, SCHF₂, NO₂, NH₂, N(R²⁹)₂, NHCOR²⁹, NHSO₂R²⁹, NHSO₂NH₂, CO₂R²⁹, and CON(R²⁹)₂; R³ is selected from the group consisting of hydrogen, halogen, C₁-C₆ linear alkyl, C₁-C₆ linear alkenyl, C₃-C₇ branched alkyl, C₃-C₇ branched alkenyl, C₃-C₇ cycloalkyl, C₁-C₆ linear alkoxy, C₃-C₇ branched alkoxy, C₃-C₇ cycloalkoxy, —S—C₁-C₆ linear alkyl, —S—C₃-C₇ branched alkyl, —S—C₃-C₇ cycloalkyl, —SO₂—C₁-C₆ linear alkyl, —SO₂—C₃-C₇ branched alkyl, —SO₂—C₃-C₇ cycloalkyl, OCHF₂, OCH₂F, SCF₃, SCHF₂, SCH₂F, NO₂, NH₂, N(R²⁹)₂, NHCOR²⁹, NHSO₂R²⁹, NHSO₂NH₂, CO₂R²⁹, and CON(R²⁹)₂; In some embodiments R¹ and R² are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R² and R³ are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R³ and R⁴ are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₁-C₆ fluoroalkyl, OR⁶, (CR^(10a)R^(10b))_(m)NHR¹¹, CR^(14a)R^(14b)NR¹⁵R¹⁶.

R⁶ is selected from the group consisting of CH₂(CH₂)_(n)NR^(7a)R^(7b),

R^(7a) and R^(7b) are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and CO₂R⁸; In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; n is 1 or 2; R⁸ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted phenyl, and optionally substituted benzyl; R⁹ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; R^(10a) and R^(10b) are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇ branched alkyl, optionally substituted C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; In some embodiments R^(10a) and R^(10b) are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring; m is 1, 2, or 3; R¹¹ is selected from the group consisting of COCR^(12a)R^(12b)(NHR¹³),

R^(12a) and R^(12b) are at each occurrence independently selected from the group consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, Cl₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; R¹³ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; Y is at each occurrence independently selected from the group consisting of H₂ and O; R^(14a) and R^(14b) are at each occurrence independently selected from the group consisting of hydrogen, CH₃, CH₂CH₃, CH(CH₃)₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(1\TH2)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH), CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring; R¹⁵ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkenyl; In some embodiments R^(14a) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; In some embodiments R^(14b) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; R¹⁶ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, COCR^(17a)R^(17b)NR^(19a)R^(19b), COCR^(17a)R^(17b)OR¹⁸, SO₂CR^(17a)R^(17b)NR^(19a)R^(19b), COCR^(17a)R^(17b)NHSO₂R^(19a),

and (CR^(23a)R^(23b))_(q)NHR²⁴;

In some embodiments R¹⁵ and R¹⁶ are taken together with the atom to which they are bound to form an optionally substituted four to six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O;

R^(17a) and R^(17b) are at each occurrence independently selected from the group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring; In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one O atom within the ring; In some embodiments R^(17a) and R¹⁸ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; In some embodiments R^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; Y¹ is at each occurrence independently selected from the group consisting of H₂, O, and —H/—OCH₂Ph; R¹⁸ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; In some embodiments R^(19a) and R^(19b) are at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl C₁-C₆ fluoroalkyl, COR²⁵, CH₂R²⁵, SO₂R²⁶, an optionally substituted four to six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O, COCHR²⁷NH₂,

In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; R²⁰ is at each occurrence independently selected from the group consisting of CH₂, O, C═O, and NH; R²¹ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; R²² is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆, alkynyl;

In some embodiments ²¹ and R²² are taken together with the atoms to which they are bound to form an optionally substituted five or six membered ring containing two nitrogen atoms;

R^(23a) and R^(23b) are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇ branched alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionally substituted. C₂-C₆ alkynyl; In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted 3 to 6 membered carbocyclic ring; R²⁴ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; q is 1, or 2; R²⁵ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R²⁶ is at each occurrence independently selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl; R²⁷ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; R²⁸ is at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl, COR²⁹, and SO₂—C₁₋₆ alkyl; R²⁹ is at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl, C₁-C₆ alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula (II):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (III):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (IV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (V):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VIII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having fonnula (IX):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (X):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XIII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XIV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVIII)

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R²⁷ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄N H₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂.

The present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient.

The present invention yet further relates to an effective amount of one or more compounds according to the present invention and an anticancer agent.

The present invention also relates to a method for treating or preventing cancer, particularly melanoma, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention, possibly in conjunction with an excipient and/or an anticancer agent.

The present invention also relates to a method for treating or preventing disease or conditions associated with cancer, particularly melanoma. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention, possibly in conjunction with an excipient and/or an anticancer agent.

Cancers that may be treated or prevented by administering to a subject an effective amount of a compound or composition according to the present invention, possibly with an excipient or an anticancer agent, include ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, skin cancer, brain cancer, and leukemia.

The present invention also relates to a method for treating or preventing various neurological or CNS states as well as depression/anxiety states in which riluzole is clinically relevant including, but are not limited to, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, and Huntington's disease, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention, possibly with an excipient or other CNS drug such as serotonin reuptake inhibitor (SRI).

The present invention yet further relates to a method of enhancing the activity of a serotonin reuptake inhibitor (SRI) in an individual in need thereof. The methods comprise co-administering to the individual an effective amount of a compound or composition according to the present invention and a SRI.

In certain embodiments, the serotonin reuptake inhibitor can be citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or combinations with other psychotropic medications including an anti-psychotic, an anticonvulsant, a tricyclic antidepressant, a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a selective serotonin-norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manic agent, or a combination of one or more of the foregoing.

The present invention further relates to a process for preparing the acyl benzo[d]thiazol-2-amine of the present invention.

These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The acyl benzo[d]thiazol-2-amine of the present invention may be useful in treating and preventing cancers such as melanoma. The novel acyl benzo[d]thiazol-2-amine of the disclosure may have enhanced stability to hepatic metabolism and may be delivered into systemic circulation by oral administration. Riluzole has demonstrated anti-melanoma activity in vitro, in mice and in a Phase 0 human clinical trial. The novel acyl benzo[d]thiazol-2-amine of the disclosure may also be useful in treating and preventing other disease states in which riluzole is clinically relevant. Such diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS) bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, metnory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, and Huntington's disease.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in andlor selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from the group consisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa unless specifically stated otherwise, In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously

As used herein, the term “halogen” shall mean chlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C₁-C₆) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (C₁-C₆ alkyl)₂amino, the alkyl groups may be the same or different.

As used herein, “cycloalkyl,” whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term “cycloalkyl” also includes carhocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo [2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., —CF₃, CF₂CF₃). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. The term v cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom e.g., tetrahydrofuran, tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may be substituted.

The term “aryl,” wherein used alone or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen -2-yl 4,5 -dimethoxy naphthylen-1-yl, and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl.” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzothranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, triazinyl, thiazolyl, 1H imidazolyl, oxazolyl, fumyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, benzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R² and R³ taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarvl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit.

Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted C₁ alkyl, trifluoromethyl is a substituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl -5-amino)octanyl is a substituted C₈ alkyl; 3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.

The variable groups defined herein, e.g., alkyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine (I), —CN, —NO₂, oxo (═O), —OR³⁰, —SR³⁰, —N(R³⁰)₂, —NR³⁰C(O)R³⁰, —SO₂R³⁰, —SO₂OR³⁰, —SO₂N(R³⁰)₂, —C(O)R³⁰, —C(O)OR³⁰, —C(O)N(R³⁰)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selected independently from halogen, —CN, —NO₂, oxo, and R³⁰; wherein R³⁰, at each occurrence, independently is hydrogen, —OR³¹, —SR³¹, —C(O)R³¹, —C(O)OR³¹, —C(O)N(R³¹)₂, —SO₂R³¹, —S(O)₂OR³¹, —N(R³¹)₂, —NR³¹C(O)R³¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R³⁰ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R³¹, at each occurrence, independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R³¹ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

—OR³²; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;

—C(O)R³²; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;

—C(O)OR³²; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;

—C(O)N(R³²)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;

—N(R³²)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);

halogen: —F, —Cl, —B, and —I;

vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2, e+g=3; for example, —CH₂F, —CH₂, —CF₃, —CCl₃, or —CBr₃;

—SO₂R³²; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;

C₁-C₆ linear, branched, or cyclic alkyl;

Cyano

Nitro;

N(R³²)C(O)R³²;

Oxo (═O);

Heterocycle; and

Heteroaryl.

wherein each R³² is independently hydrogen, optionally substituted C₁-C₆ linear or branched alkyl (e.g., optionally substituted C₁-C₄ linear or branched alkyl), or optionally substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄ cycloalkyl); or two R³² units can be taken together to form a ring comprising 3-7 ring atoms. In certain aspects, each R³² is independently hydrogen, C₁-C₆ linear or branched alkyl optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆ cycloalkyl.

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁-C₆ alkyl” is specifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,” “analog,” and “composition of matter” stand equally well for the prodrug agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts fotmed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄, Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R¹³)₂, each R¹³ may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.

As used herein, the term “anticancer agent” shall mean a compound that is useful for the treatment or prevention of cancer, including but not limited to melanoma, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, skill cancer, brain cancer, and leukemia. Non-limiting examples of anticancer agents include Vemurafenib, Ipilimumab, Masitinib, Sorafenib, Lenalidomide, Oblimersen, Trametinib, Dabrafenib, RO5185426, Veliparib, Bosentan, YM155, CNTO 5 95, CR011-vcMMAE, CY503, Lenvatinib, Avastin, Tasidotin, Ramucirumab, IPI-504, Tasisulam, KW2871, MPC-6827, RAF265, Dovitinib, Everolimus, MEK162, BKM120, Nilotinib, Reolysin, 825A, Tremelimumab, PI-88, Elesclomol, STA9090, and Allovectin-7.

Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.

The acyl benzo[d]thiazol-2-amines of the present invention are N-substituted include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R¹, R², and R⁴ are each independently selected from the group consisting of hydrogen, halogen, C₁-C₆ linear alkyl, C₁-C₆ linear alkenyl, C₃-C₇ branched alkyl, C₃-C₇ branched alkenyl, C₃-C₇ cycloalkyl, C₁-C₆ linear alkoxy, C₃-C₇ branched alkoxy, C₃-C₇ cycloalkoxy, —S—C₁-C₆ linear alkyl, —S—C₃-C₇ branched alkyl, —S—C₃-C₇ cycloalkyl, —SO₂—C₁-C₆ linear alkyl, —SO₂—C₃-C₇ branched alkyl, —SO₂—C₃-C₇ cycloalkyl, OCF₃, OCHF₂, OCH₂F, SCF₃, SCHF₂, SCH₂F, NO₂, NH₂, N(R²⁹)₂, NHCOR²⁹, NHSO₂R²⁹, NHSO₂NH₂, CO₂R²⁹, and CON(R²⁹)₂; R³ is selected from the group consisting of hydrogen, halogen, C₁-C₆ linear alkyl, C₁-C₆ linear alkenyl, C₃-C₇ branched alkyl, C₃-C₇ branched alkenyl, C₃-C₇ cycloalkyl, C₁-C₆ linear alkoxy, C₃-C₇ branched alkoxy, C₃-C₇ cycloalkoxy, —S—C₁-C₆ linear alkyl, —S—C₃-C₇ branched alkyl, —S—C₃-C₇ cycloalkyl, —SO₂—C₁-C₆ linear alkyl, —SO₂—C₃-C₇ branched alkyl, —SO₂—C₃-C₇ cycloalkyl, OCHF₂, OCH₂F, SCF₃, SCHF₂, SCH₂F, NO₂, NH₂, N(R²⁹)₂, NHCOR²⁹, NHSO₂R²⁹, NHSO₂NH₂, CO₂R²⁹, and CON(R²⁹)₂; In some embodiments R¹ and R² are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R² and R³ are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R³ and R⁴ are taken together with the atoms to which they are bound to form a ring consisting of 5 to 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₁-C₆fluoroalkyl, OR⁶, (CR^(10a)R^(10b))_(m)NHR¹¹, CR^(14a)R^(14b)NR¹⁵R¹⁶.

R⁶ is selected from the group consisting of CH₂(CH₂)NR^(7a)R^(7b),

R^(7a) and R^(7b) are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and CO₂R⁸; In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; n is 1 or 2; R⁸ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted phenyl, and optionally substituted benzyl; R⁹ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; R^(10a) and R^(10b) are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇ branched alkyl, optionally substituted C₃-C₇ cycloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl; In some embodiments R^(10a) and R^(10b) are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring; m is 1, 2, or 3; R¹¹ is selected from the group consisting of COCR^(12a)R^(12b)(NHR¹³),

R^(12a) and R^(12b) are at each occurrence independently selected from the group consisting of hydrogen, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH(OH)CH₃, CH₂Ph, CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; R¹³ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; Y is at each occurrence independently selected from the group consisting of H₂ and O; R^(14a) and R^(14b) are at each occurrence independently selected from the group consisting of hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂(CCH), CH₂(cyclohexyl), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring; R¹⁵ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₂-C₆ alkynyl; In some embodiments R^(14a) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; In some embodiments R^(14b) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; R¹⁶ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, COCR^(17a)R^(17b)NR^(19a)R^(19b), COCR^(17a)R^(17b)OR¹⁸, SO₂CR^(17a)R^(17b)NR^(19a)R^(19b), COCR^(17a)R^(17b)NHSO₂R^(19a),

and (CR^(23a)R^(23b))_(q)NHR²⁴; In some embodiments R¹⁵ and R¹⁶ are taken together with the atom to which they are bound to form an optionally substituted four to six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O; R^(17a) and R^(17b) are at each occurrence independently selected from the group consisting hydrogen, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring; In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one O atom within the ring;

In some embodiments R^(17a) and R¹⁸ are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;

In some embodiments R^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;

Y¹ is at each occurrence independently selected from the group consisting of H₂, O, and —H/—OCH₂Ph;

R¹⁸ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; In some embodiments R^(19a) and R^(19b) are at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl C₁-C₆ fluoroalkyl, CH₂R²⁵, SO₂R²⁶, an optionally substituted four to six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O, COCHR²⁷NH₂,

In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting; of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; R²⁰ is at each occurrence independently selected from the group consisting of CH₂, O, C═O, and NH; R²¹ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; R²² is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; In some embodiments R²¹ and R²² are taken together with the atoms to which they are bound to form an optionally substituted five or six membered ring containing two nitrogen atoms; R^(23a) and R^(23b) are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇ branched alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally substituted C₂-C₆ alkenyl, and optionally substituted C₂-C₆ alkynyl; In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted 3 to 6 membered carbocyclic ring; R²⁴ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; q is 1, or 2; R²⁵ is at each occurrence independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R²⁶ is at each occurrence independently selected from the group consisting of C₃-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl; R²⁷ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂CONH₂; R²⁸ is at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl, COR²⁹, and SO₂—C₁₋₆alkyl; R²⁹ is at each occurrence independently selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇ branched alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, optionally substituted aryl, optionally substituted heteroaryl, C₁-C₆ alkoxy, and C₁-C₆ alkylamino.

The compounds of the present invention include compounds having formula (II):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (III):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (IV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (V):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (VIII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (IX):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (X):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XIV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XIV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XV):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVII):

including enantiomers, diastercomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

The compounds of the present invention include compounds having formula (XVIII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R²³ is selected from the group consisting H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₃Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4—OH—Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), CH₂CO₂H, CH₂CH₂CO₂H, CH₂CONH₂, and CH₂CH₂H₂. In some embodiments R¹ is hydrogen. In some embodiments R¹ is halogen. In some embodiments R¹ is C₁-C₆ linear alkyl. In some embodiments R¹ is C₁-C₆ linear alkenyl. In some embodiments R¹ is C₃-C₇ branched alkyl. In some embodiments R¹ is C₃-C₇ branched alkenyl. In some embodiments R¹ is C₃-C₇ cycloalkyl. In some embodiments R¹ is C₁-C₆ linear alkoxy. In some embodiments R¹ is C₃-C₇ branched alkoxy. In some embodiments R¹ is C₃-C₇ cycloalkoxy. In some embodiments R¹ is —S—C₁-C₆ linear alkyl. In some embodiments R¹ is —S—C₃-C₇ branched alkyl. In some embodiments R¹ is —S—C₃-C₇ cycloalkyl. In some embodiments R¹ is —SO₂—C₁-C₆ linear alkyl. In some embodiments R¹ is —SO₂—C₃-C₇ branched alkyl. In some embodiments R¹ is —SO₂—C₃-C₇ cycloalkyl, In some embodiments R¹ is OCF₃. In some embodiments R¹ is OCHF₂. In some embodiments R¹ is OCH₂F. In some embodiments R¹ is SCF₃. In some embodiments R¹ is SCHF₂. In some embodiments R¹ is SCH₂F. In some embodiments R¹ is NO₂. In some embodiments R¹ is NH₂. In some embodiments R¹ is N(R²⁹)₂. In some embodiments R¹ is NHCOR²⁹. In some embodiments R¹ is NHSO₂R²⁹. In some embodiments R¹ is NHSO₂NH₂. In some embodiments R¹ is CO₂R²⁹. In some embodiments R¹ is CON(R²⁹)₂. In some embodiments R² is hydrogen. In some embodiments R² is halogen. In some embodiments R² is C₁-C₆ linear alkyl. In some embodiments R² is C₁-C₆ linear alkenyl. In some embodiments R² is C₃-C₇ branched alkyl. In some embodiments R² is C₃-C₇ branched alkenyl. In some embodiments R² is C₃-C₇ cycloalkyl. In some embodiments R² is C₁-C₆ linear alkoxy. In some embodiments R² is C₃-C₇ branched alkoxy. In some embodiments R² is C₃-C₇ cycloalkoxy. In some embodiments R² is —S—C₁-C₆ linear alkyl. In some embodiments R² is —S—C₃-C₇ branched alkyl. In some embodiments R² is —S—C₃-C₇ cycloalkyl. In some embodiments R² is —SO₂—C₁-C₆ linear alkyl. In some embodiments R² is —SO₂—C₃-C₇ branched alkyl. In some embodiments R² is —SO₂—C₃-C₇ cycloalkyl. In some embodiments R² is OCF₃. In some embodiments R² is OCHF₂. In some embodiments R² is OCH₂F. In some embodiments R² is SCF₃. In some embodiments R² is SCHF₂. In some embodiments R² is SCH₂F. In some embodiments R² is NO₂. In some embodiments R² is NH₂. In some embodiments R² is N(R²⁹)₂. In some embodiments R² is NHCOR²⁹. In some embodiments R² is NHSO₂R²⁹. In some embodiments R² is NHSO₂NH₂. In some embodiments R² is CO₂R²⁹. In some embodiments R² is CON(R²⁹)₂. In some embodiments R³ is hydrogen. In some embodiments R³ is halogen. In some embodiments R³ is C₁-C₆ linear alkyl. In some embodiments R³ is C₁-C₆ linear alkenyl. In some embodiments R³ is C₃-C₇ branched alkyl. In some embodiments R³ is C₃-C₇ branched alkenyl. In some embodiments R³ is C₃-C₇ cycloalkyl. In some embodiments R³ is C₁-C₆ linear alkoxy. In some embodiments R³ is C₃-C₇ branched alkoxy. In some embodiments R³ is C₃-C₇ cycloalkoxy. In some embodiments R³ is —S—C₁-C₆ linear alkyl, In some embodiments R³ is —S—C₃-C₇ branched alkyl. In some embodiments R³ is —S—C₃-C₇ cycloalkyl. In some embodiments R³ is —SO₂—C₁-C₆ linear alkyl. In some embodiments R³ is —SO₂—C₃-C₇ branched alkyl. In some embodiments R³ is —SO₂—C₃-C₇ cycloalkyl. In some embodiments R³ is OCHF₂. In some embodiments R³ is OCH₂F. In some embodiments R³ is SCF₃. In some embodiments R³ is SCHF₂. In some embodiments R³ is SCH₂F. In some embodiments R³ is NO₂. In some embodiments R³ is NH₂. In some embodiments R³ is N(R²⁹)₂. In some embodiments R³ is NHCOR²⁹. In some embodiments R³ is NHSO₂R²⁹. In some embodiments R³ is NHSO₂NH₂. In some embodiments R³ is CO₂R²⁹. In some embodiments R³ is CON(R²⁹)₂. In some embodiments R⁴ is hydrogen. In some embodiments R⁴ is halogen. In some embodiments R⁴ is C₁-C₆ alkyl. In some embodiments R⁴ is C₁-C₆ alkenyl. In some embodiments R⁴ is C₃-C₇ branched alkyl. In some embodiments R¹ is C₃-C₇ branched alkenyl. In some embodiments R⁴ is C₃-C₇ cycloalkyl. In some embodiments R⁴ is C₁-C_(6 alkoxy.) In some embodiments R⁴ is C₃-C₇ branched alkoxy. In some embodiments R⁴ is C₃-C₇ cycloalkoxy. In some embodiments R⁴ is —S—C₁-C₆ linear alkyl. In some embodiments R⁴ is —S—C₃-C₇ branched alkyl. In some embodiments R⁴ is —S—C₃-C₇ cycloalkyl. In some embodiments R⁴ is —SO₂—C₁-C₆ linear alkyl. In some embodiments R⁴ is —SO₂—C₃-C₇ branched alkyl. In some embodiments R⁴ is —SO₂—C₃-C₇ cycloalkyl. In some embodiments R⁴ is OCF₃. In some embodiments R⁴ is OCHF₂. In some embodiments R⁴ is OCH₂F. In some embodiments R⁴ is SCF₃. In some embodiments R⁴ is SCHF₂. In some embodiments R⁴ is SCH₂F. In some embodiments R⁴ is NO₂. In some embodiments R⁴ is NH₂. In some embodiments R⁴ is N(R²⁹)₂. In some embodiments R⁴ is NHCOR²⁹. In some embodiments R⁴ is NHSO₂R²⁹. In some embodiments R⁴ is NHSO₂NH₂. In some embodiments R⁴ is CO₂R¹⁹. In some embodiments R⁴ is CON(R²⁹)₂. In some embodiments R¹ and R² are taken together with the atoms to which they are bound to form a ring consisting of 5 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments R¹ and R² are taken together with the atoms to which they are bound to form a ring consisting of 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R² and R³ are taken together with the atoms to which they are bound to form a ring consisting of 5 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R² and R³ are taken together with the atoms to which they are bound to for u a ring consisting of 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R³ and R⁴ are taken together with the atoms to which they are bound to form a ring consisting of 5 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments, R³ and R⁴ are taken together with the atoms to which they are bound to form a ring consisting of 6 atoms, optionally containing up to two members selected from the group consisting of nitrogen, oxygen, and sulfur; In some embodiments R⁵ is C₁-C₆ alkyl. In some embodiments R⁵ is C₃-C₇ branched alkyl. In some embodiments R⁵ is C₃-C₇ cycloalkyl. In some embodiments R⁵ is C₁-C₆ fluoroalkyl. In some embodiments R⁵ is OR⁶. In some embodiments R⁵ is (CR^(10a)R^(10b))_(m)NHR¹¹. In some embodiments R⁵ is CR^(14a)R^(14b)NR¹⁵R¹⁶. In some embodiments R⁵ is

In some embodiments R⁵ is

In some embodiments R⁵ is

In some embodiments R⁶ is CH₂(CH₂)_(n)NR^(7a)R^(7b). In some embodiments R⁶ is

In some embodiments R^(7a) is hydrogen. In some embodiments R^(7a) is C₁-C₆ alkyl. In some embodiments R^(7a) is C₃-C₇ branched alkyl. In some embodiments R^(7a) is C₃-C₇ cycloalkyl. In some embodiments R^(7a) is C₂-C₆ alkenyl. In some embodiments R^(7a) is C₂-C₆ alkynyl. In some embodiments R^(7a) is CO₂R⁸. In some embodiments R^(7b) is hydrogen. In some embodiments R^(7b) is C₁-C₆ alkyl. In some embodiments R^(7b) is C₃-C₇ branched alkyl. In some embodiments R^(7b) is C₃-C₇ cycloalkyl. In some embodiments R^(7b) is C₂-C₆ alkenyl. In some embodiments R^(7b) is C₂-C₆alkynyl. In some embodiments R^(7b) is CO₂R⁸. In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted three membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂;

In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted four membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂;

In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted five membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; In some embodiments R^(7a) and R^(7b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from thegroup consisting of O, NR⁹, S, and SO₂; In some embodiments n is 1. In some embodiments n is 2. In some embodiments R⁸ is C₁-C₆ alkyl. In some embodiments R⁸ is C₃-C₇ branched alkyl. In some embodiments R⁸ is C₃-C₇ cycloalkyl. In some embodiments R⁸ is C₂-C₆ alkenyl. In some embodiments R⁸ is C₂-C₆ alkynyl. In some embodiments R⁸ is optionally substituted phenyl. In some embodiments R⁸ is optionally substituted benzyl. In some embodiments R⁹ is C₁-C₆ alkyl. In some embodiments R⁹ is C₃-C₇ branched alkyl. In some embodiments R⁹ is C₃-C₇ cycloalkyl. In some embodiments R⁹ is, C₂-C₆ alkenyl. In some embodiments R⁹ is C₂-C₆ alkynyl. In some embodiments R^(10a) is hydrogen. In some embodiments R^(10a) is optionally substituted C₁-C₆ alkyl. In some embodiments R^(10a) is optionally substituted C₃-C₇ branched alkyl. In some embodiments R^(10a) is optionally substituted C₃-C₇ cycloalkyl. In some embodiments R^(10a) is C₂-C₆ alkenyl. In some embodiments R^(10a) is C₂-C₆ alkynyl. In some embodiments R^(10b) is hydrogen. In some embodiments R^(10b) is optionally substituted C₁-C₆ alkyl. In some embodiments R^(10b) is optionally substituted C₃-C₇ branched alkyl. In some embodiments R^(10b) is optionally substituted C₃-C₇ cycloalkyl. In some embodiments R^(10b) is C₂-C₆ alkenyl. In some embodiments R^(10b) is C₂-C₆ alkynyl. In some embodiments R^(10a) and R^(10b) are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring. In some embodiments m is 1. In some embodiments m is 2. In some embodiments m is 3. In some embodiments R¹¹ is COCR^(12a)R^(12b)(NHR¹³). In some embodiments R¹¹ is

In some embodiments R¹¹ is

In some embodiments R^(12a) is hydrogen. In some embodiments R^(12a) is CH₃. In some embodiments R^(12a) is CH(CH₃)₂. In some embodiments R^(12a) is CH₂CH(CH₃)₂. In some embodiments R^(12a) is CH(CH₃)CH₂CH₃. In some embodiments R^(12a) is CH₂OH. In some embodiments R^(12a) is CH(OH)CH₃. In some embodiments R^(12a) is CH₂Ph. In some embodiments R^(12a) is CH₂(4—OH—Ph). In some embodiments R^(12a) is (CH₂)₄NH₂. In some embodiments R^(12a) is (CH₂)₃NHC(NH₂)NH. In some embodiments R^(12a) is CH₂(3-indole). In some embodiments R^(12a) is CH₂(5-imidazole). In some embodiments R^(12a) is CH₂CO₂H. In some embodiments R^(12a) is CH₂CH₂CO₂H. In some embodiments R^(12a) is CH₂CONH₂. In some embodiments R^(12a) is CH₂CH₂CONH₂. In some embodiments R^(12b) is hydrogen. In some embodiments R^(12b) is CH₃. In some embodiments R^(12b) is CH(CH₃)₂. In some embodiments R^(12b) is CH₂CH(CH₃)₂. In some embodiments R^(12b) is CH(CH₃)CH₂CH₃. In some embodiments R^(12b) is CH₂OH. In some embodiments R^(12b) is CH(OH)CH₂. In some embodiments R^(12b) is CH₂Ph. In some embodiments R^(12b) is CH₂(4—OH—Ph). In some embodiments R^(12b) is (CH₂)₄NH₂. In some embodiments R^(12b) is (CH₂)₃NHC(NH₂)Ntl. In some embodiments R^(12b) is CH₂(3-indole). In some embodiments R^(12b) is CH₂(5-imidazole). In some embodiments R^(12b) is CH₂CO₂H. In some embodiments R^(12b) is CH₂CH₂CO₂H. In some embodiments R^(12b) is CH₂CONH₂. In some embodiments R^(12b) is CH₂CH₂CONH₂. In some embodiments R¹³ is hydrogen. In some embodiments R¹³ is C₁-C₆ alkyl. In some embodiments R¹³ is C₃-C₇ branched alkyl. In some embodiments R¹³ is C₃-C₇ cycloalkyl. In some embodiments R¹³ is C₂-C₆ alkenyl. In some embodiments R¹³ is C₂-C₆ alkenyl. In some embodiments Y is H₂. In some embodiments Y is O. In some embodiments R^(14a) is hydrogen. In some embodiments R^(14a) is CH₃. In some embodiments R^(14a) is CH₂CH₃. In some embodiments R^(14a) is CH(CH₃)₂. In some embodiments R^(14a) is CH₂CH(CH₃)₂. In some embodiments R^(14a) is CH(CH₃)CH₂CH₃. In some embodiments R^(14a) is CH₂OH. In some embodiments R^(14a) is CH₂OCH₂Ph. In some embodiments R^(14a) is CH(OH)CH₃. In some embodiments R^(14a) is CH₂Ph. In some embodiments R^(14a) is CH₂(4—OH—Ph). In some embodiments R^(14a) is (CH₂)₄NH₂. In some embodiments R^(14a) is (CH₂)₃NHC(NH₂)NH. In some embodiments R^(14a) is CH₂(3-indole). In some embodiments R^(14a) is CH₂(5-imidazole). In some embodiments R^(14a) is CH₂(CCH). In some embodiments R^(14a) is CH₂(cyclohexyl). In some embodiments R^(14a) is CH₂CO₂H. In some embodiments R^(14a) is CH₂CH₂CO₂H. In some embodiments R^(14a) is CH₂CONH₂. In some embodiments R^(14a) is CH₂CH₂CONH₂. In some embodiments R^(14b) is hydrogen. In some embodiments R^(14b) is CH₃. In some embodiments R^(14b) is CH₂CH₃. In some embodiments R^(14b) is CH(CH₃)₂. In some embodiments R^(14b) is CH₂CH(CH₃)₂. In some embodiments R^(14b) is CH(CH₃)CH₂CH₃. In some embodiments R^(14b) is CH₂OH. In some embodiments R^(14b) is C₂OCh₂Ph. In some embodiments R^(14b) is CH(OH)CH₃. In some embodiments R^(14b) is CH₂Ph. In some embodiments R^(14b) is CH₂(4—OH—Ph). In some embodiments R^(14b) is (CH₂)₄NH₂. In some embodiments R^(14b) is (CH₂)₃NHC(NH₂)NH. In some embodiments R^(14b) is CH₂(3-indole). In some embodiments R^(14b) is CH₂(5-imidazole). In some embodiments R^(14b) is CH₂(CCH). In some embodiments R^(14b) is CH₂(cyclohexyl). In some embodiments R^(14b) is CH₂CO₂H. In some embodiments R^(14b) is CH₂CH₂CO₂H. In some embodiments R^(14b) is CH₂CONH₂. In some embodiments R^(14b) is CH₂CH₂CONH₂. In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted three membered saturated carbocyclic ring. In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted four membered saturated carbocyclic ring. In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted five membered saturated carbocyclic ring. In some embodiments R^(14a) and R^(14b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated carbocyclic ring. In some embodiments R¹⁵ is hydrogen. In some embodiments R¹⁵ is C₁-C₆ alkyl. In some embodiments R¹⁵ is C₃-C₇ branched alkyl. In some embodiments R¹⁵ is C₃-C₇ cycloalkyl. In some embodiments R¹⁵ is C₂-C₆ alkenyl. In some embodiments R¹⁵ is C₁-C₆ haloalkyl. In some embodiments R¹⁵ is and C₂-C₆alkynyl. In some embodiments R^(14a) and R¹⁵ are taken together with the atoms to which they are bound to for u an optionally substituted four membered ring containing one nitrogen atom; In some embodiments R^(14a) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted five membered ring containing one nitrogen atom; In some embodiments R^(14a) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted six membered ring containing one nitrogen atom; In some embodiments R^(14b) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted four membered ring containing one nitrogen atom; In some embodiments R^(14b) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted five membered ring containing one nitrogen atom; In some embodiments R^(14b) and R¹⁵ are taken together with the atoms to which they are bound to form an optionally substituted six membered ring containing one nitrogen atom; In some embodiments R¹⁶ is hydrogen. In some embodiments R¹⁶ is C₁-C₆ alkyl. In some embodiments R¹⁶ is COCR^(17a)R^(17b)NR^(19a)R^(19b). In some embodiments R¹⁶ is COCR^(17a)R^(17b)OR¹⁸. In some embodiments R¹⁶ is SO₂CR^(17a)R^(17b)NR^(19a)R^(19b). In some embodiments R¹⁶ is COCR^(17a)R^(17b)NHSO₂R^(19a). In some embodiments R¹⁶ is,

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is

In some embodiments R¹⁶ is (CR^(23a)R^(23b))_(q)NHR²⁴. In some embodiments R¹⁵ and R¹⁶ are taken together with the atom to which they are bound to form an optionally substituted four membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O. In some embodiments R¹⁵ and R¹⁶ are taken together with the atom to which they are bound to form an optionally substituted five membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O. In some embodiments R¹⁵ and R¹⁶ are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O. In some embodiments R^(17a) is hydrogen. In some embodiments R^(17a) is CH₃. In some embodiments R^(17a) is CH₂CH₃. In some embodiments R^(17a) is CH₂CH₂CH₃. In some embodiments R^(17a) is CH₂CCH. In some embodiments R^(17a) is CH(CH₃)₂. In some embodiments R^(17a) is CH₂CH(CH₃)₂. In some embodiments R^(17a) is CH(CH₃)CH₂CH₃. In some embodiments R^(17a) is CH₂OH. In some embodiments R^(17a) is CH₂OCH₂Ph. In some embodiments R^(17a) is CH₂CH₂OCH₂Ph. In some embodiments R^(17a) is CH(OH)CH₃. In some embodiments R^(17a) is CH₂Ph. In some embodiments R^(17a) is CH₂(cyclohexyl). In some embodiments R^(17a) is CH₂(4—OH—Ph). In some embodiments R^(17a) is (CH₂)₄NH₂. In some embodiments R^(17a) is (CH₂)₃NHC(NH₂)NH. In some embodiments R^(17a) is CH₂(3-indole). In some embodiments R^(17a) is CH₂(5-imidazole). In some embodiments R^(17a) is CH₂CO₂H. In some embodiments R^(17a) is CH₂CH₂CO₂H. In some embodiments R^(17a) is CH₂CONH₂. In some embodiments R^(17a) is CH₂CH₂CONH₂. In some embodiments R^(17b) is hydrogen. In some embodiments R^(17b) is CH₃. In some embodiments R^(17b) is CH₂CH₃. In some embodiments R^(17b) is CH₂CH₂CH₃. In some embodiments R^(17b) is CH₂CCH. In some embodiments R^(17b) is CH(CH₃)₂. In some embodiments R^(17b) is CH₂CH(CH₃)₂. In some embodiments R^(17b) is CH(CH₃)CH₂CH₃. In some embodiments R^(17b) is CH₂OH. In some embodiments R^(17b) is CH₂OCH₂Ph. In some embodiments R^(17b) is CH₂CH₂OCH₂Ph. In some embodiments R^(17b) is CH(OH)CH₃. In some embodiments R^(17b) is CH₂Ph. In some embodiments R^(17b) is CH₂(cyclohexyl). In some embodiments R^(17b) is CH₂(4—OH—Ph). In some embodiments R^(17b) is (CH₂)₄NH₂. In some embodiments R^(17b) is (CH₂)₃NHC(NH₂)NH. In some embodiments R^(17b) is CH₂(3-indole). In some embodiments R^(17b) is CH₂(5-imidazole). In some embodiments R^(17b) is CH₂CO₂H. In some embodiments R^(17b) is CH₂CH₂CO₂. In some embodiments R^(17b) is CH₂CONH₂. In some embodiments R^(17b) is CH₂CH₂CONH₂. In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted three membered saturated carbocyclic ring. In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to for u an optionally substituted four membered saturated carbocyclic ring. In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted five membered saturated carbocyclic ring. In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated carbocyclic ring. In some embodiments R^(17a) and R^(17b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one O atom within the ring. In some embodiments R^(17a) and R^(17b) are taken together with the atoms to which they are bound to form an optionally substituted four membered ring containing one nitrogen atom. In some embodiments R^(17a) and R¹⁸ are taken together with the atoms to which they are bound to form an optionally substituted five membered ring containing one nitrogen atom. In some embodiments R^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted six membered ring containing one nitrogen atom. In some embodiments R^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted four membered ring containing one nitrogen atom. In some embodiments RR^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted five membered ring containing one nitrogen atom. In some embodiments R^(17a) and R^(19a) are taken together with the atoms to which they are bound to form an optionally substituted six membered ring containing one nitrogen atom. In some embodiments Y¹ is H₂. In some embodiments Y¹ is O. In some embodiments Y¹ is —H/—OCH₂Ph. In some embodiments R¹⁸ is of hydrogen. In some embodiments R¹⁸ is C₁-C₆ alkyl. In some embodiments R¹⁸ is C₃-C-₇ branched alkyl. In some embodiments R¹⁸ is C₃-C₇ cycloalkyl. In some embodiments R¹⁸ is C₂-C₆ alkenyl. In some embodiments R¹⁸ is C₂-C₆ alkenyl. In some embodiments R^(19a) is H. In some embodiments R^(19a) is, C₁-C₆ alkyl In some embodiments R^(19a) is C₃-C₇ branched alkyl. In some embodiments R^(19a) is C₃-C₇ cycloalkyl. In some embodiments R^(19a) is C₂-C₆ alkenyl, In some embodiments R^(19a) is C₂-C₆ alkynyl. In some embodiments R^(19a) is C₁-C₆ fluoroalkyl. In some embodiments R^(19a) is COR²⁵. In some embodiments R^(19a) is CH₂R²⁵. In some embodiments R^(19a) is SO₂R²⁶. In some embodiments R^(19a) is an optionally substituted four membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19a) is an optionally substituted five membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19a) is an optionally substituted six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19a) is COCHR²⁷NH₂. In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19a) is

In some embodiments R^(19b) is H. In some embodiments R^(19b) is, C₁-C₆ alkyl In some embodiments R^(19b) is C₁-C₇ branched alkyl. In some embodiments R^(19b) is C₃-C₇ cycloalkyl. In some embodiments R^(19b) is C₂-C₆ alkenyl. In some embodiments R^(19b) is C₂-C₆ alkynyl. In some embodiments R^(19b) is C₁-C₆ fluoroalkyl. In some embodiments R^(19b) is COR²⁵. In some embodiments R^(19b) is CH₂R²⁵. In some embodiments R^(19b) is SO₂R²⁶. In some embodiments R^(19b) is an optionally substituted four membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19b) is an optionally substituted five membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19b) is an optionally substituted six membered. saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR²⁸ and O. In some embodiments R^(19b) is COCHR²⁷NH₂. In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19b) is

In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted three membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted four membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted five membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; In some embodiments R^(19a) and R^(19b) are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR⁹, S, and SO₂; In some embodiments R²⁰ is CH₂. In some embodiments R²⁰ is O. In some embodiments R²⁰ is C═O. In some embodiments R²⁰ is NH. In some embodiments R²¹ is hydrogen. In some embodiments R²¹ is C₁-C₆ alkyl. In some embodiments R²¹ is C₃-C₇ branched alkyl. In some embodiments R²¹ is C₃-C₇ cycloalkyl. In some embodiments R²¹ is C₂-C₆ alkenyl. In some embodiments R²¹ is C₂-C₆ alkynyl. In some embodiments R²² is hydrogen. In some embodiments R²² is C₁-C₆ alkyl. In some embodiments R²² is C₃-C₇ branched alkyl. In some embodiments R²² is C₃-C₇ cycloalkyl. In some embodiments R²² is C₂-C₆ alkenyl. In some embodiments R²² is C₂-C₆ alkynyl. In some embodiments R²¹ and R²² are taken together with the atoms to which they are bound to form an optionally substituted five membered ring containing two nitrogen atoms. In some embodiments R²¹ and R²² are taken together with the atoms to which they are bound to form an optionally substituted six membered ring containing two nitrogen atoms. In some embodiments R^(23a) is hydrogen. In some embodiments R^(23a) is optionally substituted C₁-C₆ alkyl. In some embodiments R^(23a) is optionally substituted C₃-C₇ branched alkyl. In some embodiments R^(23a) is optionally substituted C₃-C₇ cycloalkyl. In some embodiments R^(23a) is optionally substituted C₂-C₆ alkenyl. In some embodiments R^(23a) is optionally substituted C₂-C₆ alkynyl. In some embodiments R^(23b) is hydrogen. In some embodiments R^(23b) is optionally substituted C₁-C₆ alkyl. In some embodiments R^(23b) is optionally substituted C₁-C₇ branched alkyl. In some embodiments R^(23b) is optionally substituted C₃-C₇ cycloalkyl. In some embodiments R^(23b) is optionally substituted C₂-C₆ alkenyl. In some embodiments R^(23b) is optionally substituted C₂-C₆ alkynyl. In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted 3 membered carbocyclic ring. In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted 4 membered carbocyclic ring. In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted r membered carbocyclic ring. In some embodiments R^(23a) and R^(23b) are taken together with the atom to which they are bound to form an optionally substituted 6 membered carbocyclic ring. In some embodiments R²⁴ is hydrogen. In some embodiments R²⁴ is C₁-C₆ alkyl. In some embodiments R²⁴ is C₃-C₇ branched alkyl. In some embodiments R²⁴ is C₃-C₇ cycloalkyl. In some embodiments R²⁴ is C₂-C₆ alkenyl. In some embodiments R²⁴ is C₂-C₆ alkynyl. In some embodiments q is 1. In some embodiments q is 2. In some embodiments R²⁵ is hydrogen In some embodiments R²⁵ is C₁-C₆ alkyl. In some embodiments R²⁵ is C₃-C₇ branched alkyl. In some embodiments R²⁵ is C₃-C₇ cycloalkyl. In some embodiments R²⁵ is C₂-C₆ alkenyl. In some embodiments R²⁵ is C₂-C₆ alkynyl. In some embodiments R²⁵ is C₁-C₆ fluoroalkyl. In some embodiments R²⁵ is optionally substituted aryl. In some embodiments R²⁵ is optionally substituted heteroaryl. In some embodiments R²⁶ is C₁-C₆ alkyl. In some embodiments R²⁶ is C₃-C₇ branched alkyl. In some embodiments R²⁶ is C₃-C₇ cycloalkyl. In some embodiments R²⁶ is C₂-C₆ alkenyl. In some embodiments R²⁶ is C₂-C₆ alkynyl. In some embodiments R²⁶ is optionally substituted aryl. In some embodiments R²⁶ is optionally substituted heteroaryl. In some embodiments R²⁷ is hydrogen. In some embodiments R²⁷ is CH₃. In some embodiments R²⁷ is CH₂CH₃. In some embodiments R²⁷ is CH₂CH₂CH₃. In some embodiments R²⁷ is CH₂CCH. In some embodiments R²⁷ is CH(CH₃)₂. In some embodiments R²⁷ is CH₂CH(CH₃)₂. In some embodiments R²⁷ is CH(CH₃)CH₂CH₃. In some embodiments R²⁷ is CH₂OH. In some embodiments R²⁷ is CH₂OCH₂Ph. In some embodiments R²⁷ is CH₂CH₂OCH₂Ph. In some embodiments R²⁷ is CH(OH)CH₃. In some embodiments R²⁷ is CH₂Ph. In some embodiments R²⁷ is CH₂(cyclohexyl). In some embodiments R²⁷ is CH₂(4—OH—Ph). In some embodiments R²⁷ is(CH₂)₄NH₂. In some embodiments R²⁷ is(CH₂)₃NHC(NH₂)NH. In some embodiments R²⁷ is CH₂(3-indole). In some embodiments R²⁷ is CH₂(5-imidazole). In some embodiments R²⁷ is CH₂CO₂H. In some embodiments R²⁷ is CH₂CH₂CO₂H. In some embodiments R²⁷ is CH₂CONH₂. In some embodiments R²⁷ is CH₂CH₂CONH₂. In some embodiments R²⁸ is hydrogen. In some embodiments R²⁸ is C₁-C₆ alkyl. In some embodiments R²⁸ is C₃-C₇ branched alkyl. In some embodiments R²⁸ is C₃-C₇ cycloalkyl. In some embodiments R²⁸ is C₂-C₆ alkenyl. In some embodiments R²⁸ is C₂-C₆ alkynyl. In some embodiments R²⁸ is optionally substituted aryl. In some embodiments R²⁸ is optionally substituted heteroaryl. In some embodiments R²⁸ is COR²⁹. In some embodiments R²⁸ is SO₂—C₁₋₆alkyl. In some embodiments R²⁹ is hydrogen. In some embodiments R²⁹ is C₁-C₆ alkyl. In some embodiments R²⁹ is C₃-C₇ branched alkyl. In some embodiments R²⁹ is C₃-C₇ cycloalkyl. In some embodiments R²⁹ is C₂-C₆ alkenyl. In some embodiments R²⁹ is C₂-C₆ alkynyl. In some embodiments R²⁹ is optionally substituted aryl. In some embodiments R²⁹ is optionally substituted heteroal. In some embodiments R²⁹ is C₁-C₆alkoxy. In some embodiments R²⁹ is C₁-C₆alkylamino. Non-limiting exemplary embodiments of compounds having the formula (I) or a pharmaceutically acceptable salt form thereof are herein described in table 1 below:

TABLE 1 Non-limiting exemplary compounds of the disclosure. Entry Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

For the purposes of the present invention, a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

For the purposes of the present invention, a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.

Process

Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.

Compounds of formula (I) may be prepared according to the process outlined in schemes 1-21.

A compound of the formula (1), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafitiorophosphate, N,N′-dicyclohexyl carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). A compound of the formula (3) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (4).

A compound of the formula (4) is reacted with a compound of the formula (5), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetratriethyluronium hexialluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorphohne and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (6). A compound of the formula (6) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (7).

A compound of the formula (4) is reacted with a compound of (8), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodlimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofbran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9).

A compound of the formula (4) is reacted with a compound of (10), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronitmi hexaffuorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylaminotmethylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (11). A compound of the formula (11) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (12).

A compound of the formula (4) is reacted with a compound of (13), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).

A compound of the formula (4) is reacted with a compound of (15), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16). A compound of the formula (16) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (17).

A compound of the formula (1), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (18), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (19). A compound of the formula (19) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (20).

A compound of the formula (20) is reacted with a compound of (21), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azahenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrothran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (22).

A compound of the formula (20) is reacted with a compound of (23), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexalluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4 dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24). A compound of the formula (24) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (25).

A compound of the formula (20) is reacted with a compound of (26), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methyimorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (27).

A compound of the formula (20) is reacted with a compound of (28), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (29). A compound of the formula (29) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (30).

A compound of the formula (20) is reacted with a compound of (31), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexatluorophosphate, N,N′-dicyclohcxylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azaberizotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32). A compound of the formula (32) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (33).

A compound of the foiinula (20) is reacted with a compound of (34), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylfomiainide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (35). A compound of the formula (35) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (36).

A compound of the formula (20) is reacted with a compound of (37), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl) -N,N,N′,N′-tetratnethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide 1-ethyl-3-(3 -dimethy laminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azahenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (38). A compound of the formula (38) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, and the like in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of the formula (39).

A compound of the formula (25) is reacted with a compound of (40), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (41).

A compound of the formula (42), a known compound or a compounds prepared by known methods, is reacted with triphosgene in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride, chloroform, and the like. The resulting product is then reacted with a compound of the formula (1) in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (43). A compound of the formula (44) is reacted with hydrogen bromide in the presence of acetic acid, optionally in the presence of a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44).

A compound of the formula (45), a known compound or a compounds prepared by known methods, is reacted with triphosgene in the presence of a solvent such as as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride, chloroform, and the like to provide a compound of the formula (46). A compound of the formula (46) is reacted with a compound of the formula (1) in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like, in the presence of a solvent such as N,N-dimethylformatnide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (43).

A compound of the formula (48), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (49), a known compound or a compounds prepared using known methods, in the presence of a solvent such as as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (50).

A compound of the formula (51), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (52), a known compound or a compounds prepared usingknown methods, in the presence of a solvent such as as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (53).

A compound of the formula (54), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (55), a known compound or a compounds prepared using known methods, in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in the presence of a solvent such as as N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (56). A compound of the formula (56) is reacted with a compound of the formula (57), a known compound or a compounds prepared by known methods, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (58).

A compound of the formula (56) is reacted with a compound of the formula (59), a known compound or a compounds prepared by known methods wherein M is a counter ion such as sodium, potassium, tetrabutyl ammonium, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60). A compound of the formula (60) is reacted with hydrogen in the presence of a catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, to provide a compound of the formula (61). A compound of the formula (61) is reacted with a compound of the formula (62), a known compound or a compound prepared by known methods, in the presence of a hydride source such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy-borohydride, and the like, optionally in the presence of an acid such as acetic acid, trifluoroacetic acid, formic acid, and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (63). A compound of the formula (63) is reacted with a compound of the formula (62), a known compound or a compound prepared by known methods, in the presence of a hydride source such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, and the like, optionally in the presence of an acid such as acetic acid, trifluoroacetic acid, formic acid, and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the fonnula (64).

Schemes 1-21 describe the preparation of compounds containing chiral centers. Those skilled in the art of organic synthesis will recognize that the chemistry described in schemes 1-21 can be applied to prepare the enantiomer of the compounds described employing starting material containing the opposite stereochemistry. In the case of compounds with multiple chiral centers those skilled in the art of organic synthesis will recognize that the chemistry described in schemes 1-21 can be employed to prepare compounds of the disclosure from starting materials containing the desired chirality and each chiral center.

EXAMPLES

The examples illustrate methods for preparing representative compounds of formula (I). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.

The following procedures are employed to purify and analyze compounds of the disclosure. Those skilled in the art would understand that alternate methods could be employed to analyze and purify the compounds of the disclosure.

Method A: LC/MS data are determined with a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode array detector from 210-400 nm; the solvent system is 5-95% acetonitrile in water (with 0.1% TFA) over nine minutes using a linear gradient, and retention times are in minutes. Mass spectrometry is performed on a Waters ZQ using electrospray in positive mode.

Method B: Preparative reversed phase HPLC is performed on a Waters Sunfire column (19×50 mm, C18, 5μm) with a 10 min mobile phase gradient of 10% acetonitrile/water to 90% acetonitrile/water with 0.1% TFA as buffer using 214 and 254 nm as detection wavelengths. Injection and fraction collection are performed with a Gilson 215 liquid handling apparatus using Trilution LC software.

Method C: LC/MS data are determined on a Shimadzu LC 20AD instrument with a Phenomenex Luna C18 (3 μm) 50×3.0 mm column. The mobile phase consists of water and acetonitrile with 0.1% formic acid buffer. Gradient is 10-90% acetonitrile over three minutes and held at 90% acetonitrile for two minutes. Detection is performed on diode array detector from 210-400 nm and retention times are in minutes. Mass spectra are determined on an Applied Biosystems MDS Sciex API 2000 instrument using electrospray ionization.

Formulations

The present invention also relates to compositions or formulations which comprise the acyl benzo[d]thiazol-2-amines according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more of the acyl benzo[d]thiazol-2-amines and salts thereof according to the present invention which are effective and one or more excipients.

For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and finictional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

The present invention also provides pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Clennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

Compounds of the present invention can be administered orally, parenterally or as orally dissolvable tablets (“ODT's”) or sublingual preparations neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known prodrug agents. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, ODTs or other sublingual formulations, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxatner 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also he suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds of the present invention into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

To increase the effectiveness of compounds of the present invention, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

Compounds of the present invention can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present invention accordingly provides methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings melding its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more acyl benzo[d]thiazol-2-amine according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more acyl benzo[d]thiazol-2-amine according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more acyl benzo[d]thiazol-2-amine according to the present invention; and one or more excipients.

Procedures

The following procedures can be utilized in evaluating and selecting acyl benzo[d]thiazol-2-amines of the present disclosure.

Stability in Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF). Procedure from Baudy et. al. (J. Med. Chem. 2009, 52, 771-778) are used. The physiological stability of the acyl benzo[d]thiazol-2-amines is determined by examining the stability of the compound in SGF, and SIF at 37° C. The compounds are prepared in a 9:1 mixture of the appropriate test component (SGF, SIF) and acetonitrile to a final concentration of 0.01 mg/mL. The samples are thoroughly mixed and maintained at 37° C. Each sample is injected consecutively onto an Agilent 1100 system (Luna C18, 3 μM, 50 mm×3 mm; 1 mL/min; mobile phase; mobile phase of 0.1% trifluoroacetic acid in water/0.1% trifluoroacetic acid in acetonitrile) after a 3 hour period. The percent remaining of acyl benzo[d]thiazol-2-amine is then calculated. The identities of the parent compounds and conversion products are confirmed by LC/MS.

Plasma Stability: Assessment of plasma stability is carried out by individual incubations of a compound of the disclosure in fresh mouse or human control plasma at a concentration of 1 uM for 1 hour at 37° C. After which, the samples are de-proteinized by addition of 2 volumes of acetonitrile containing 0.1% formic acid and internal standard, vortex mixed for 2 minutes and centrifuged at 4000 rpm for 10 minutes to pellet precipitated protein. The resulting supernatant containing the drug candidates is diluted 5-fold with water containing 0.1% formic acid and submitted to LC-MS/MS analysis. All determinations are done in triplicate. Plasma stability is expressed as percent of control remaining.

Metabolic Stability: In vitro metabolic stability are determined in pooled mouse or human liver microsomes (BD Gentest) at a protein concentration of 0.5 mg/mL in reaction buffer (100 mM KH₂PO₄, pH 7.4 and 12 mM MgCl₂). Each a compound of the disclosure is added to a final concentration of 1 uM. This mixture is pre-warmed to 37° C. for 10 minutes prior to starting the reaction with the addition of β-Nicotinamide adenine dinucleotide 2′-phosphate reduced (NADPH) to a final concentration of 1 mM. A parallel incubation lacking NADPH served as the control. After incubation for 30 minutes at 37° C., the reactions are quenched by the addition of acetonitrile containing 0.1% formic acid and internal standard, vortex mixed for 2 minutes and centrifuged at 4000 rpm for 10 minutes to pellet the precipitated protein. The resulting supernatant containing the compound of the disclosure and its potential metabolites is diluted 5-fold with water containing 0.1% formic acid and submitted to LC-MS/MS analysis. Metabolic stability is expressed as percent of control remaining.

LC-MS/MS Analysis: An aliquot from each incubation is analyzed by LC-MS/MS with SRM detection in the positive ionization mode using an ABSciex API 5500 QTrap Mass Spectrometer interfaced via the ABSciex Turbo V IonSpray source (ESI) to an Eksigent ExpressHT LC system. Best peak shape and separation from interfering matrix species is afforded by an Eksigent 3C18-CL-300, 3μ, 50×1 mm column. A fast gradient, from 15 to 85% organic in 2.5 minutes, with run time of 5.0 minutes, and flow rate of 50 uL/min is utilized. Peak areas are integrated using MultiQuant v2.0 software from ABSciex.

Rat Pharmacokinetic studies of the compounds of the disclosure: The pharmacokinetics of the compounds of the disclosure are evaluated following either a single intravenous or oral administration of the prodrug to fasted male Sprague-Dawley rats at suggested close levels (mg/Kg body weight). Blood samples are collected at pre-determined time points including a 0 hour time point and usually between 7 and 8 additional time points not exceeding a 24 hour period. Plasma concentrations of the compound of the disclosure and its metabolites are determined by LC-MS/MS and pharmacokinetic parameters are determined using WinNonlin (v6.3).

Plasma samples are extracted and analyzed using the methods described in Plasma Sample Extraction and Analysis. All data are expressed as ng/mL of the free base. Samples that are below the limit of quantification (0.5 ng/mL) are not used in the calculation of averages.

Pharmacokinetic parameters are calculated from the time course of the plasma concentrations. Pharmacokinetic parameters are determined with Phoenix Winnonlin (v6.3) software using a non-compartmental model. The maximum plasma concentration (Cmax) and time to the maximum plasma concentration (Tmax) of the compound of the disclosure are observed from the data. The area under the concentration-time curve (AUC) of the compound of the disclosure is calculated using the trapezoidal formula with calculation to the last quantifiable data point, and to infinity if applicable. Plasma half-life (t½) is calculated from 0.693/slope of the terminal elimination phase. Mean residence time, MRT, is calculated by dividing the area under the moment curve (AUMC) by the AUC. Any samples below the limit of quantitation (0.5 ng/mL) are treated as zero for pharmacokinetic data analysis.

Plasma Sample Extraction and Analysis: Analytical stock solutions (1.00 mg/mL of the free compound of the disclosure) are prepared in DMSO. Standards are prepared in diluted matrix containing 1 part 10% formic acid and 9 parts Sprague-Dawley rat plasma containing sodium heparin as the anticoagulant (pre-diluted with 1 part of 0.5M citric acid and 9 parts whole blood). Working solutions are prepared in 50:50 acetonitrile:water. Working solutions are then added to plasma to make calibration standards to final concentrations of 1000, 500, 100, 50, 10, 5, 1, and 0.5 ng/mL. Standards contain the compound of the disclosure. Standards are treated identically to the study samples.

Sample Extraction: Plasma samples are extracted via acetonitrile precipitation on a Tomtec Quadra 96-Model 320 liquid handling system in a 96-well plate format.

Step 1

Standards: Add 10 μL of appropriate working solution to 50 μL of blank matrix in a 96-well plate.

Blanks: Add 10 μL 50:50 acetonitrile:water to 50 82 L of blank matrix in a 96-well plate.

Samples: Add 10 μL 50:50 acetonitrile:water to 50 μL of study sample in a 96-well plate.

Cap and mix.

Step 2: Using the Tomtec, add 50 μL of sample to 150 μL of acetonitrile (containing 100 ng/mL propranolol as an internal standard) that has been pre-loaded onto a Sirocco Protein Precipitation plate (Waters Corp.)

Step 3: Using the Tomtec, mix the samples via air aspiration

Step 4: Apply vacuum and collect filtrates into clean polypropylene 96-well plate, Cap for analysis.

HPLC Conditions:

Instrument: Waters Acquity UPLC

Column: Waters Acquity BEH C18, 100×2.1 mm id, 1.7 μm

Mobile Phase Buffer: 40 mM ammonium formate, pH 3.5

Aqueous Reservoir (A): 10% buffer, 90% water

Organic Reservoir (B): 10% buffer, 90% acetonitrile

Gradient Program:

Time (min) Grad. Curve % A % B 0.00 6 90 10 3.75 6 0 100 4.00 6 90 10 5.00 6 90 10

Flow Rate: 400 μL/min

Injection Volume: 5 μL

Run Time: 5.0 min

Column Temperature: 40° C.

Sample Temperature: 8° C.

Strong Autosampler Wash: 1:1:1(v:v:v) water:methanol:isopropanol with 0.2% formic acid

Weak Autosampler Wash: 4 mM ammonium formate

Mass Spectrometer Conditions

Instrument: PE Sciex API4000

Interface: Electrospray (“Turbo Ion Spray”)

Mode: Multiple Reaction Monitoring (MRM)

Gases: CUR 30, CAD 10, GS1 50, GS2 50

Source Temperature: 550° C.

Polarity: positive

Inhibition of glutamate release and proliferation in human melanoma cells. Studies on mouse and human melanoma cells (specifically C8161 cels) showed higher levels of released glutamate than normal melanocytes. (Cancer Res 2007; 67: 2298-2305). Treatment of C8161 cells with riluzole inhibits excess cellular gluatamate.

Measurement of extracellular glutamate: Amplex Red Glutamic Acid/Glutamate Oxidase assay kit (Invitrogen-Mo-35 lecular Probes) is used to measure the amount of glutamate released in the medium. Cells are grown in medium devoid of glutamate and glutamine but supplemented with GlutaMax (2 mmol/L) for 3 days. Cells are plated at 10³ cells per well with 200 μL of medium containing specific compounds with concentrations ranging from 0.01 μM to 50 μM in 96-well plate. After each day from 1-5 days, 100 of medium are collected for measurement of the amount of glutamate released according to the manufacturer's protocol.

Cellular proliferation assay: The cells are treated with 10, 20, 30, 40, or 50 μmol/L of a compound of the disclosure. Riluzole is used as a positive where dose-dependent suppression of C8161 cell growth is detected in comparison with no treatment and DMSO treated. Cell viability is measure by standard MIT cell proliferation assays using 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheny ltetrazolium bromide (MTT) assays are done according to the manufacturer's protoco (Roche).

Inhibition of Human Melanoma Cell Xenograft Growth by compounds of the disclosure: Melanoma C8161 cells are inoculated subcutaneously into nude mice at 10 per site. The mice are treated with 7.5 mg/kg riluzole (control), an equimolar amount of a compound of the disclosure, and a dose of a compound of the disclosure threefold lower in molar terms than the dose of riluzole, by oral gavage when tumor volume had reached 6 mm³. Mice are treated every day for 21 days, and tumor sizes are measured twice weekly with a Vernier caliper.

Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, although the compounds are described and claimed as including pharmaceutically acceptable salts, it is intended in accordance with the present invention that enantiomers, diastereomers, hydrates, solvates and complexes thereof also be included. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination. 

1-18. (canceled)
 19. A composition comprising an effective amount of at least one compound according to claim 31 and at least one excipient.
 20. (canceled)
 21. A method for treating or preventing cancer, said method comprising administering to a subject an effective amount of at least one compound according to claim
 31. 22. The method of claim 22, wherein the at least one compound is administered in a composition further comprising an anticancer agent.
 23. The method of claim 23 wherein the anticancer agent is selected from Vemurafenib, Ipilimumab, Masitinib, Sorafenib, Lenalidomide, Oblimersen, Trametinib, Dabrafenib, RO5185426, Veliparib, Bosentan, YM155, CNTO 5 95, CR011-vcM MAE, CY503, Lenvatinib, Avastin, Tasidotin, Ramucirumab, IPI-504, Tasisulam, KW2871, MPC-6827, RAF265, Dovitinib, Everolimus, MEK162, BKM120, Nilotinib, Reolysin, 825A, Tremelimumab, PI-88, Elesclomol, STA9090, and Allovectin-7.
 24. The method of claim 22 wherein the cancer is selected from the group consisting of melanoma, nonmelanoma skin cancer, skin cancer, ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, brain cancer including glioma and glioblastoma, and leukemia.
 25. A method for treating or preventing a non-cancerous disease in which riluzole is clinically relevant said method comprising administering to a subject an effective amount of at least one compound according to claim
 31. 26. The method of claim 25, wherein the disease in which riluzole is clinically relevant is selected from amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxia associated with Anti-GAD antibodies target and onconeural antigen, essential tremor, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, and Huntington's disease.
 27. A method of attenuating presynaptic glutamate release said method comprising administering to a subject an effective amount of at least one compound according to claim
 31. 28. A method of normalizing, enhancing, or potentiating the uptake of glutamate by glia, said method comprising administering to a subject an effective amount of at least one compound according to claim
 31. 29. A method for treating or preventing disease in which riluzole is clinically relevant, said method comprising administering to a subject an effective amount of at least one compound according to claim 31 and a serotonin reuptake inhibitor.
 30. The method of claim 29 wherein the disease in which riluzole is clinically relevant, is selected from amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, hereditary spinocerebellar ataxia, spinocerebellar ataxia, sporadic ataxia, episodic ataxia, Friedreich Ataxia, Multisystem Atrophy, ataxia associated with Anti-GAD antibodies target and onconeural antigen, essential tremor, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, and Huntington's disease.
 31. A compound having a structure according to formula (IX):

including pharmaceutically acceptable salts thereof, wherein: R¹, R² and R³ are each independently hydrogen or halo; R⁴ is hydrogen; R^(14a) and R^(14b) are hydrogen; R¹⁵ is C₁-C₆ alkyl; R^(17a) and R^(17b) are hydrogen; R^(19a) is C₁-C₆ alkyl; and R^(19b) is hydrogen.
 32. The compound according to claim 31 selected from: 